Pharmacological enhancement of immune responses for the treatment of disease, particularly viral and bacterial infections and cancer, is attractive for several reasons. Beyond the obvious observation that the immune system is generally responsible for clearing pathogens, the breadth of an immune response offers the potential to react to infectious disease with a low risk of developing drug resistance. Also, immune-based therapy offers the potential to address the treatment of infections where direct replication inhibitors are either absent or unsatisfactory. Some viruses offer only poor prospects for development of effective agents directed at virally encoded targets due to their replication strategies, while others are so genetically plastic that the inhibitory effect of a direct replication inhibitor is lost rapidly, unless effective strategies are taken to suppress the evolution of resistant variants.
Several clinical observations support the importance of tumor immune surveillance in humans. The increased risk of tumor development in immunosuppressed patients, cases of spontaneous tumor regression, and the presence of tumor-reactive T cells and B cells correlating with improved prognosis all point to a role for the immune system in controlling tumor growth. Studies comparing histopathology with clinical outcome for early-stage lesions in several cancer types have demonstrated that intratumoral lymphocyte infiltrates are strongly correlated with reduced frequencies of metastasis (Taylor et al. J. CLIN. ONC. 25(7):869-75 (2007)) and improved patient survival (Sharma et al. PNAS 104(10):3967-72 (2007)). It is clear that the balance between stimulation and suppression of the host immune response plays an essential role in the ability of cancer cells to grow, invade, and metastasize. Recognition and elimination of these malignant cells is a major challenge for the host immune system. Two reasons that immune control of tumor growth is inadequate are that tumors are capable of locally suppressing host immunity and many tumors are intrinsically poorly immunogenic. Immunotherapy has had some success in treating selected tumors and the potential to harness the immune system as a therapeutic modality remains of great interest to many oncologists. First generation immunotherapies were single cytokines, such as Interferon-α (IFN-α) for the treatment of melanoma and renal cell carcinoma (Moschos et al. CANCER TREAT. RES. 126:207-41 (2005)). With this approach, the number of patients who responded to therapy was small, but for those who did, the response could be profound and sometimes curative.
The advent of molecular biology has enabled products based on interferon (“IFN”), an immune cytokine, which is a component in the treatment of hepatitis C virus (“HCV”) infection and in the treatment of some tumors. The biological importance of IFN in antiviral host defense and in cancer therapy has spawned many efforts to identify agents that stimulate endogenous IFN production. Stimulation of IFN production has been reported with agonists of Toll-like receptors (“TLRs”), which has accelerated efforts to exploit them for therapeutic benefit. TLRs are a family of pathogen-recognition receptors that when activated by appropriate agonists (e.g., LPS, viral double-stranded RNA, flagellin, etc.) activate the innate immune response (Iwasaki and Medzhitov, NAT. IMMUNOL. 5(10):987-95 (2004)). Stimulation of TLRs either directly or indirectly leads to: (i) the release of multiple cytokines, including type I and type II interferons; (ii) the induction of pathways and enzymes that destroy intracellular pathogens; and (iii) the maturation of professional antigen-presenting cells, resulting in the activation of the innate and adaptive immune response. The benefit of many of these responses in the treatment of viral diseases and cancers, notably stimulation of type I and type II interferons and NK and T cell activation, is well-recognized. To date, 10 functional TLRs have been identified in humans.
In general, drugs are administered as immediate-release dosage forms so that the entire dose of the drug is released within a very short period of time following administration. As the bolus of released drug is absorbed, the plasma drug concentration rapidly rises to a maximal or peak concentration and subsequently declines as the drug undergoes “clearance”. During some portion of the time period in which the plasma drug concentration rises, peaks and subsequently declines, the drug provides its therapeutic effects, i.e., the plasma drug concentration achieves or exceeds a therapeutically effective concentration for the disease or condition being treated. Likewise, the therapeutic effect disappears when the plasma drug concentration and physiological response thereto declines to a level that is below a certain threshold. These principals hold true not only for drugs administered orally but also for drugs administered by intravenous bolus and for many small molecules when administered by subcutaneous injection.
In certain instances, drugs are delivered in slow-release form, in an attempt to sustain plasma drug levels so as to sustain the duration of benefits. In these cases, the duration of benefit again tracks with the duration of drug exposure. In other instances, typically with agonists that activate rather than inhibit their respective targets, benefit persists beyond the duration of drug exposure. For example, activation of a host receptor can lead to activation of cellular responses, the benefit of which can persist beyond the period of time in which the receptor is activated by circulating drug levels.
In all the cases cited above, immediate release, sustained release and agonists with a durable period of action, it is expected that the magnitude of beneficial effects correlates with the amount of drug administered, i.e. more administered drug leads to more benefit.
For drugs administered in this fashion, relatively high peaks and low valleys of plasma concentrations cannot be avoided. Accordingly, doses and dosing intervals can be selected to help obtain an acceptable balance between average steady-state plasma drug concentrations that provide effective therapy and avoiding, as much as possible, problematical peak and/or trough plasma concentrations during each dosing interval. Typically the minimal acceptable dosing frequency for a particular drug is set by constraints imposed by toxicity and efficacy. Dosing too often results in toxicity, and dosing too infrequently is inefficacious. For example, the response in genotype 1 infected HCV patients to administration of IFN-α in combination with ribavirin demonstrates that benefit increases with duration of exposure during a standard treatment interval. Specifically, daily dosing of standard interferons induces a substantially more rapid initial decline in viral load than does three times weekly (“TIW”) administration of the same agent (deLedinghen et al., J. HEPATOL., 36(6):819-26 (2002); Perez et al., J. VIRAL HEPAT., 10(6):437-45 (2003)). Furthermore, sustained viral response increases with use of sustained exposure interferon (e.g. pegylated interferon) when compared to TIW administration of standard interferons, which are cleared relatively rapidly (33-36% for standard interferons to 42-46% for sustained exposure interferons (Maims et al., NAT. REV. DRUG DISCOV., 6(12):991-1000 (2007)). Surprisingly, while daily dosing or continuous exposure is optimal for IFN-α, it is suboptimal for TLR agonists generally, TLR7 agonists and TLR7 agonist prodrugs and the treatment of viral infection in particular.